Regulation of hematopoietic stem cell function by prenatal folate status

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Prenatal folate status predicts risk for a range of adult diseases, including cardiovascular disease, obesity, and colon cancer, but the driving pathogenic mechanisms are unknown. The proposed work will test the hypothesis that maternal folate status programs risk for inflammation-related disease across the lifespan in offspring by altering hematopoietic stem cell (HSC) function from development onwards. Folate-mediated one carbon metabolism provides the sole source of one-carbons for nucleotide biosynthesis and cellular methylation reactions. Impaired folate status due to altered dietary intake or common genetic polymorphisms affects proliferation, genomic stability, and, most notably, epigenetic regulation. Given that adult HSC function is altered by changes in epigenetic regulation, metabolism, and DNA damage, we hypothesize that early perturbations in folate status will influence HSC development and function by influencing these parameters during fetal development. We have recently shown that prenatal immune perturbation can shape long-term hematopoiesis and immune function by influencing both the composition and output of HSCs postnatally. Here, we will maintain mice on folic acid (FA) deficient or FA-supplemented diet throughout gestation, and test the effects of manipulating folate status on hematopoietic development and adult HSC function. In Aim 1, we will determine the immediate impact of maternal folate status on fetal folate metabolism, fetal hematopoiesis, and fetal HSC function by transplantation. In Aim 2, we will test how modified folate status in the prenatal period influences hematopoiesis and HSC function into adulthood. Our data will provide novel information on how early life conditions program HSC function and output across the lifespan.